Domain V peptides inhibit β2-glycoprotein I mediated mesenteric ischemia/reperfusion-induced tissue damage and inflammation1

Reperfusion of ischemic tissue induces significant tissue damage in multiple conditions, including myocardial infarctions, stroke and transplantation. Although not as common, the mortality rate of mesenteric ischemia/reperfusion (IR) remains over 70%. Although complement and naturally occurring antibodies are known to mediate significant damage during IR, the target antigens are intracellular molecules. We investigated the role of the serum protein, β2-glycoprotein I as an initiating antigen for antibody recognition and β2-GPI peptides as a therapeutic for mesenteric IR. The time course of β2-GPI binding to the tissue indicated binding and complement activation within 15 min post-reperfusion. Treatment of wildtype mice with peptides corresponding to the lipid binding domain V of β2-GPI blocked intestinal injury and inflammation, including cellular influx and cytokine and eicosanoid production. The optimal therapeutic peptide (peptide 296) contained the lysine rich region of domain V. In addition, damage and most inflammation was also blocked by peptide 305 which overlaps with peptide 296 but does not contain the lysine rich, phospholipid binding region. Importantly, peptide 296 retained efficacy after replacement of Cys residues with Ser. In addition, infusion of wildtype serum containing reduced levels of anti-β2-GPI antibodies into Rag-1−/− mice prevented IR-induced intestinal damage and inflammation. Together these data suggest that the serum protein,β2-GPI initiates the IR-induced intestinal damage and inflammatory response and as such is a critical therapeutic target for IR-induced damage and inflammation. This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org